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    Corticosteroid-binding globulin regulates cortisol pharmacokinetics.

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    Authors
    Perogamvros, Ilias
    Aarons, Leon
    Miller, A G
    Trainer, Peter J
    Ray, David W
    Affiliation
    Department of Endocrinology, Christie Hospital and Endocrine Sciences Research Group, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK . School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK . Department of Biochemistry, University Hospital of South Manchester, Wythenshawe, UK.
    Issue Date
    2010-11-05
    
    Metadata
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    Abstract
    Objective:  Corticosteroid-binding globulin (CBG) is the principal carrier for cortisol in the circulation. Variations in CBG binding capacity are predicted to alter total serum cortisol disposition, but free serum cortisol is believed to be unaffected. Unbound cortisol pharmacokinetics (PK) have not been studied in the context of CBG changes. We aimed to assess the regulation of cortisol PK by CBG. Design and subjects:  Women on oestrogens (OCP), patients homozygous for a non-functioning CBG variant (CBG null) and healthy controls (HV) were studied before and after IV and oral administration of hydrocortisone 20mg. Measurements:  PK parameters were studied for total serum cortisol (SerF), free serum cortisol (FreeF) and cortisone (FreeE), and salivary cortisol (SalF) and cortisone (SalE): area under the curve (AUC), clearance (CL), half-life, and volume of distribution (Vd). Results:  Following IV hydrocortisone, AUC and half-life of SerF were significantly higher in the OCP group and lower in the CBG null. SerF CL and Vd were significantly lower in the OCP group and increased in the CBG null, compared to HV. PK parameters for FreeF and the salivary biomarkers were not different between the CBG null and HV, although OCP patients still had higher AUC compared to HV and prolonged half-life. These findings were confirmed following oral hydrocortisone, but concentration-time profiles were highly heterogeneous and SalF interpretation was problematic due to oral contamination. Conclusions:  We have demonstrated that CBG has a distinct effect on cortisol PK. When CBG binding is disrupted, FreeF retains normal PK characteristics, although CBG null patients lack a CBG-bound pool of readily releasable cortisol. Women on oestrogens may have altered free serum cortisol kinetics and thus may be potentially overexposed to glucocorticoids.
    Citation
    Corticosteroid-binding globulin regulates cortisol pharmacokinetics. 2010: Clin Endocrinol
    Journal
    Clinical Endocrinology
    URI
    http://hdl.handle.net/10541/115808
    DOI
    10.1111/j.1365-2265.2010.03897.x
    PubMed ID
    21054475
    Type
    Article
    Language
    en
    ISSN
    1365-2265
    ae974a485f413a2113503eed53cd6c53
    10.1111/j.1365-2265.2010.03897.x
    Scopus Count
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    All Christie Publications
    Endocrinology

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